Presenilins, β-amyloid precursor protein and the molecular basis of Alzheimer's disease

Abstract

Progressive cerebral deposition of the 40- and 42-residue amyloid β-proteins is an early and invariant event in all forms of Alzheimer's disease (AD). Aβ proteins are generated from the β-amyloid precursor protein (APP) via two sequential cleavages by proteases designated β-secretase and γ-secretase and are constitutively secreted by essentially all cells throughout life. APP can undergo these cleavages during its secretory trafficking to the cell surface, yet much of Aβ appears to be generated after APP reaches the surface, i.e. in the endosomal pathway. Presenilin (PS) 1 and 2, homologous proteins with eight transmembrane (TM) domains, play a critical role in the γ-secretase cleavage of APP. Deletion of presenilin 1 (PS1) in mice markedly decreases Aβ production, whereas AD-causing PS1 mutations selectively increase Aβ 42 production, thereby markedly accelerating amyloid plaque formation, both in humans and transgenic mice. Small amounts of APP and PS can be co-immunoprecipitated from cells, suggesting a direct role of PS1 in the cleavage of APP by γ-secretase. We recently observed and mutated two unusual intramembranous aspartate residues in TM6 and TM7 of each presenilin, resulting in complete blockage of the γ-secretase cleavage of APP, with no detectable Aβ production by cells. Because our protease inhibitor studies suggest that γ-secretase is an aspartyl protease, we hypothesize that these two key aspartates serve as the active site of an unprecedented intramembranous aspartyl protease (i.e. γ-secretase). The recent discovery that Notch, a protein critical for cell fate determination during development, also undergoes an intramembranous cleavage mediated by PS suggests that presenilin may be a key regulatory enzyme for several vital proteolytic events. Thought of in this context, AD may arise late in the post-reproductive life of humans as an ancillary metabolic consequence of a proteolytic mechanism which confers strong evolutionary advantage. Specific and potent inhibitors of γ-secretase/presenilin or of the recently cloned β-secretase may well prove useful for the treatment and the prevention of AD.